Abstract

Background

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed for improving vision in people with DMO.

Objectives

To assess the effectiveness, safety and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DMO.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to June 2012), EMBASE (January 1980 to June 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2012.

Selection criteria

We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment, or no treatment in patients with DMO. We also included economic evaluations to assess cost-effectiveness.

Data collection and analysis

Two review authors independently extracted the data. The risk ratio (RR) of visual loss and visual gain of three or more lines was estimated at least six months after treatment. Each economic analysis was described narratively using a structured format.

Main results

Eleven studies provided data on three comparisons of interest in this review. Compared with grid laser photocoagulation, there was evidence of moderate quality that antiangiogenic therapy (bevacizumab: two studies, 167 participants; ranibizumab: two studies, 300 participants; aflibercept: one study, 221 participants, 89 used for data extraction) more than doubled and, respectively, reduced by at least two thirds, the chance of gaining or losing 3 or more lines of vision (RR: 3.20, 95% confidence interval (CI) 2.07 to 4.95 and RR: 0.13, 95% CI: 0.05 to 0.34, respectively). In meta-analyses, no significant subgroup difference could be demonstrated between bevacizumab, ranibizumab and aflibercept regarding our primary outcome, but, again, there was little power to detect a difference. The quality of the evidence was moderate since the overall size was suboptimal for investigating between study, as well as between drug, heterogeneity.

Regarding absolute benefit, eight out of 100 patients with DMO would gain 3 or more lines of visual acuity using photocoagulation, whereas 26 would do so with antiangiogenic therapy, meaning that 100 patients need to be treated with antiangiogenic therapy to allow 18 more people (95% CI from 9 to 32) to markedly improve their vision after one year.

Using mean visual acuity outcome, the meta-analytic difference between antiangiogenic therapy and photocoagulation was 1.3 lines (1 to 1.6) after one year, favouring drug therapy.

In other analyses, ranibizumab was more effective than sham (three studies on 497 participants) and ranibizumab associated with laser was more effective than laser alone (three studies on 783 participants).

Systemic and ocular adverse events were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation (nine studies, 104 events in 2159 participants) did not show a significant difference regarding arterial thromboembolic events (RR: 0.85 (0.56 to 1.28). Similarly, no difference was suggested regarding overall mortality (53 events, RR: 0.95 (0.52 to 1.74), but clinically significant differences could not be ruled out.

Authors' conclusions

There is moderate quality evidence that antiangiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DMO, i.e. grid laser photocoagulation, or no treatment when laser is not an option. The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences. Most data were obtained at one year, and a long-term confirmation is needed, since DMO is a chronic condition. Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.

Plain language summary

Antiangiogenic therapy for diabetic macular oedema

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. The retina at the macula thickens and this can cause gradual loss of central vision. Grid or focal laser photocoagulation is effective in treating DMO and has been used for several years, but vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed to try to improve vision in people with DMO. Anti-VEGF drugs are delivered by an injection in the vitreous cavity of the eye and need to be repeated for maintenance.

We included 11 studies in this review comparing intravitreal antiangiogenic therapy with sham, laser photocoagulation or investigating its effect when added to photocoagulation. About one in five or seven more people gained a good amount of vision, i.e. 3 lines, using antiangiogenic therapy compared with laser, using seven to 10 intraocular injections in the first year, and two in the second year. Little is known about treatment needs beyond this term. Two related UK-based economic evaluations disagreed on whether ranibizumab was cost-effective compared with laser photocoagulation. The evaluation finding ranibizumab not cost-effective was revised while this review was being updated, leading the UK National Institute of Health and Clinical Excellence (NICE) to recommend ranibizumab for patients with visual impairment and more severe oedema on optical coherence tomography.

Antiangiogenic treatment was well tolerated in these studies, but since all studies were short- or medium-term, we were unable to investigate long-term effects as well as risks.